A point mutation in the thiopurine S-methyltransferase gene that led to exon 5 deletion in the transcribed mRNA

Lee, Chun Kiat; Lee, Hong Kai; Huan, Pei Tee; Chiu, Lily-Lily; Loh, Tze Ping; Koay, Evelyn Siew-Chuan

doi:10.1515/cclm-2015-1170

Cited by 3 publications

(1 citation statement)

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“…There are a few reports of proven or suspected deviating splicing patterns caused by SNPs in TPMT. Using next generation sequencing, a deletion of exon 5 was reported together with TPMT*34 (located in exon 5) and the intron mutation c.366+58T>C [37]. However, no phenotype or patient data were described in that study, and the extra band appearing in the gel analysis was not sequenced.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden

Kahlin

Helander

Skoglund

et al. 2019

Biochemical Pharmacology

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Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patient's TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.

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Section: Discussionmentioning

confidence: 99%